Brain and Behavioral Indicators of Risk for Parkinsonism among Adolescents with Early Pesticide Exposure

早期接触农药的青少年帕金森病风险的大脑和行为指标

• 批准号: 10321251
• 负责人: F. DuBois Bowman
• 金额: $ 56.61万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321251
• 关键词: 12 year old; 18 year old; 20 year old; Adolescent; Adult; Age; Age-Years; Appearance; Autonomic Dysfunction; Base of the Brain; Behavioral; Biological Markers; Birth; Blood; Bradykinesia; Brain; Brain imaging; Brain scan; Characteristics; Child; Chlorpyrifos; Clinical; Cognitive deficits; Cohort Studies; Communities; Data; Development; Diagnosis; Dystonia; Early identification; Environmental Exposure; Environmental Health; Environmental Risk Factor; Etiology; Exposure to; Functional disorder; Future; Gait; High Prevalence; Image; Individual; Insecticides; Intervention; Life; Magnetic Resonance Imaging; Measures; Modality; Modeling; Motor; Multimodal Imaging; Nerve Degeneration; Neurologic; Neurologic Signs; Occupational; Organophosphates; Parkinson Disease; Parkinsonian Disorders; Participant; Pathogenicity; Pattern; Persons; Pesticides; Population; Prevalence; Prevention strategy; Procedures; Process; Prospective Studies; Public Health; REM Sleep Behavior Disorder; Reporting; Research; Risk; Role; Rotation; Sampling; Signal Transduction; Societies; Substantia nigra structure; Symptoms; Testing; Time; Toxic Environmental Substances; Tremor; Umbilical Cord Blood; Walking; Work; age related neurodegeneration; arm; base; behavior measurement; behavior test; cohort; disorder risk; early detection biomarkers; high risk; inner city; innovation; member; minority children; motor disorder; motor symptom; multimodality; neural patterning; neurodevelopment; neuroimaging; neuromelanin; non-motor symptom; novel; novel marker; novel strategies; pesticide exposure; potential biomarker; pre-clinical; prenatal; prenatal exposure; progressive neurodegeneration; sex; urban minority; virtual

Multiple studies have demonstrated an association between organophosphate (OP) insecticide exposure and Parkinson's Disease (PD) in adults, but virtually no studies have explored signs of the pathogenic process that begins long before the appearance of motor symptoms. There is a clear need for prospective studies, including biomarkers of exposure and brain-based measures, to substantiate a cause-effect relationship and the development of parkinsonism over time. We have access to a well-characterized community sample—an urban minority birth cohort that has been followed for 18 years, with a prenatal blood biomarker of exposure to a common OP pesticide, chlorpyrifos (CPF), and regular assessments of neurodevelopment, including multimodal brain scans at 12-14 and 18 years. In this cohort, we have shown that prenatal CPF exposure is associated with motor delay at 2-3 years, and persistent brain, behavioral and subtle motor effects through 11- 12 years of age. We now have a unique opportunity to study the emergence of pre-clinical/non-motor indicators of PD risk at 18-20 years of age in this cohort. We propose to test the novel hypothesis that prenatal CPF exposure has long-term motor consequences, including neurological signs and brain-based biomarkers of PD risk that are measureable early in the pathogenic process, prior to the identification of clinically confirmed symptoms or diagnosis. We aim to: (1) conduct a single wave of neurological and brain imaging assessment (using known indicators of PD risk in adult populations) in a subset of the cohort (n=200) at 18-20 years of age. We hypothesize that those with higher prenatal CPF levels as compared to those with lower levels will show significantly more signs of early PD risk, as indicated by (a) higher prevalence of pre-clinical extrapyramidal motor dysfunction (dystonia, bradykinesia, arm tremor); (b) higher prevalence of non-motor symptoms (REM sleep behavior disorder, autonomic dysfunction, olfactory deficits); and (c) increased prodromal motor markers (gait variability, inconsistent walking pattern, arm swing asymmetry and lower axial rotation smoothness); (2) conduct structural MRI for neuromelanin to identify substantia nigra involvement (a biomarker of PD) in these same subjects. We hypothesize that those with higher prenatal CPF levels as compared to those with lower levels will show significantly greater substantia nigra involvement marked by a greater decrease in neuromelanin content; (3) employ an innovative statistical procedure using a vast number of functional and structural brain characteristics, based on multi-modal imaging data previously collected at 12-14 and 18 years, to determine whether an exposure-related pattern of neural deficits across modalities (a potential biomarker for PD) can be detected in our young cohort. We hypothesize that subjects with higher prenatal CPF levels as compared to those with lower levels will show a distinctive pattern of brain anomalies across modalities and time. This study has the potential to shift the research paradigm from a focus on neurodegenerative processes in PD to incorporate a neurodevelopmental perspective, with potential implications for future interventions.

多项研究表明，接触有机磷 (OP) 杀虫剂与 成人帕金森病 (PD)，但实际上没有研究探索其致病过程的迹象 早在运动症状出现之前就开始了。显然需要进行前瞻性研究，包括 暴露的生物标志物和基于大脑的测量，以证实因果关系和 随着时间的推移帕金森症的发展。我们可以获得一个特征明确的社区样本—— 已跟踪 18 年的城市少数民族出生队列，其产前血液生物标志物暴露于 一种常见的 OP 农药毒死蜱 (CPF)，以及神经发育的定期评估，包括 12-14 岁和 18 岁的多模式脑部扫描。在这个队列中，我们已经证明产前 CPF 暴露是 与 2-3 岁的运动迟缓相关，以及 11-11 岁持续的大脑、行为和微妙的运动影响 12 岁。我们现在有一个独特的机会来研究临床前/非运动的出现 该队列中 18-20 岁的 PD 风险指标。我们建议测试产前的新假设 CPF 暴露会产生长期的运动后果，包括神经系统体征和基于大脑的生物标志物 在鉴定临床确诊之前，可在致病过程的早期测量 PD 风险 症状或诊断。我们的目标是：（1）进行单波神经和脑成像评估 （使用成年人群中已知的 PD 风险指标）在 18-20 岁的队列子集 (n=200) 中进行。 我们假设，与产前 CPF 水平较低的人相比，产前 CPF 水平较高的人会表现出 早期 PD 风险的迹象明显更多，如 (a) 临床前锥体外系的患病率较高所示 运动功能障碍（肌张力障碍、运动迟缓、手臂震颤）； (b) 非运动症状（REM 睡眠行为障碍、植物神经功能障碍、嗅觉缺陷）； (c) 前驱运动标志物增加 （步态变异、行走模式不一致、手臂摆动不对称以及轴向旋转平滑度较低）； (2) 对神经黑色素进行结构 MRI 以确定黑质受累情况（PD 的生物标志物） 相同的科目。我们假设，与出生前 CPF 水平较低的人相比，出生前 CPF 水平较高的人 水平将显示出明显更多的黑质受累，其特征是 神经黑色素含量； (3) 采用创新的统计程序，利用大量的功能和数据 大脑结构特征，基于之前在 12-14 岁和 18 岁收集的多模态成像数据， 确定跨模式是否存在与暴露相关的神经缺陷模式（潜在的生物标志物 PD）可以在我们的年轻群体中检测到。我们假设产前 CPF 水平较高的受试者为 与那些水平较低的人相比，将显示出跨模式的独特大脑异常模式 时间。这项研究有可能改变研究范式，不再关注神经退行性过程 在 PD 中融入神经发育视角，对未来的干预措施具有潜在影响。